DESCRIPTION: Dysregulated cell growth is a hallmark characteristic of cancer cells, apparently caused by a combination of genetic changes which increase cell proliferation, decrease cell death, and cause abnormal responses to cellular growth factors. The gene product defective in the cancer-prone disorder, Ataxia-telangiectasia (AT), appears to play a significant role in cellular growth control, cancer predisposition, and cellular responses to irradiation. Unfortunately, insights into specific mechanisms and roles of this gene product have been limited by the fact that most studies have had to utilize either patient-derived EBV-immortalized or SV40-transformed cells, thus restricting adequate studies of many important cellular processes. The gene responsible for this pleiotropic disorder, ATM, has recently been cloned. Full length and fragments of human and mouse ATM cDNAs will be used to generate numerous different cell types with altered ATM expression or function and will than be utilized to better study the role of ATM in cell cycle control, growth factor responses, radiosensitivity, p53 induction, NF-kB activity, cellular senescence and apoptosis. Whether ATM overexpression alters growth control or leads to a radioresistance and whether this is a potential mechanism of radioresistance in human tumor cells will also be evaluated. Finally, the functional domains of the ATM protein will be evaluated to ascertain whether different domains control different cellular processes. These investigations will provide novel insights into the roles and mechanisms of the ATM gene product and, in the process, should shed light on mechanisms involved in cellular responses to irradiation, carcinogenesis, and cellular growth and death controls. These studies also have therapeutic implications since inhibition of ATM function should cause increased tumor cell death in response to a number of anti-neoplastic therapies.